US12049483B2ActiveUtilityA1
Selective and noncovalent inhibitors of oncogenic RAS mutants
Est. expiryDec 5, 2040(~14.4 yrs left)· nominal 20-yr term from priority
A61P 35/00C07B 2200/13A61K 38/00C07K 2319/21C07K 2319/50C07K 2319/00C07K 2319/43C07K 14/78C07K 2319/60C07K 14/82C07K 14/4702
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References
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Claims
Abstract
Provided are proteins or peptides, which may be referred to as monobodies. Fusion proteins and proteolysis targeting chimeras (PROTACs) comprising the proteins or peptides are also provided. Also provided are compositions of the proteins or peptides of the present disclosure, as well as compositions of fusion proteins and compositions of PROTACs. Methods of treating an individual in need of treatment are also provided. The methods may be to treat an individual suffering from or suspected of having KRAS(G12V), KRAS(G12S), KRAS(G12A) and/or KRAS(G12C)-associated cancers. A method may be for inhibiting ERK activation and/or proliferation of KRAS(G12V), KRAS(G12S), KRAS(G12A) and/or KRAS(G12C)-associated cancers.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A protein or peptide comprising:
i) the following sequence:
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFKVPGSKSTATIS GLKPGVDYTITVYARGYSKQGPYKPSPISINYRT (12VC1) (SEQ ID NO:1) or a truncated variant thereof;
or
ii) a variant of SEQ ID NO:1 with at least 90% homology to SEQ ID NO:1 or a truncated variant thereof,
wherein the truncated variant of i) or ii) has up to the first four residues at the N-terminus removed.
2. The protein or peptide according to claim 1 , wherein one or more of the proteins or peptides are disposed on a bead or resin or membrane.
3. The protein or peptide according to claim 1 , wherein one or more of the proteins or peptides are conjugated to a yeast display.
4. The protein or peptide according to claim 1 , wherein the protein or peptide is non-covalently bound and/or covalently conjugated to one or more other proteins and peptides such that a dimer, trimer, or oligomer is formed.
5. The protein or peptide according to claim 1 , wherein the protein or peptide is fused to a larger protein or peptide.
6. The protein or peptide according to claim 5 , wherein the larger protein or peptide is GFP, a GFP variant, yeast Aga2, or an epitope tag.
7. The protein or peptide according to claim 1 , wherein the variant is:
(SEQ ID NO: 2)
VSSVPTELEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSRSTATISGLEPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 3)
VSSVPTELEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFA
VPGSRSTATISGLEPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 4)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYIIAYGETGHGVGAFQAFR
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 5)
VSSVPTKLEVVAATPTSLLISWDAPAVTVAFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 6)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFAYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 7)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYAITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 8)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVIAYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 9)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGAGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 10)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAAQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 11)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFAAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 12)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAAK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 13)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFA
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 14)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VAGSKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 15)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPASKSTATISGLKPGVDYTITVYARGYSKQGPYKPSPISINYRT;
(SEQ ID NO: 16)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARAYSKQGPYKPSPISINYRT;
(SEQ ID NO: 17)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGASKQGPYKPSPISINYRT;
(SEQ ID NO: 18)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGAYKPSPISINYR;
(SEQ ID NO: 19)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPAKPSPISINYRT;
(SEQ ID NO: 20)
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGSKSTATISGLKPGVDYTITVYARGYSKQGPYAPSPISINYRT;
or a truncated variant thereof,
wherein the truncated variant has up to the first four residues at the N-terminus removed.
8. The protein or peptide according to claim 1 , wherein the protein or peptide is modified at a sidechain of one or more amino acid residue(s), the C-terminus, the N-terminus, or a combination thereof.
9. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO:1 comprises a sequence where at least the following underlined amino acid residues of SEQ ID NO:1 are not replaced with a different amino acid residue:
(SEQ ID NO: 1)
VSSVPTKLEVVAATPTSLLISWDAPAVTVF F Y V ITYGETGHG V GA F QA F
KVPGSKSTATISGLKPGVDYTITV Y A RG YSKQGP Y KPSPISINYRT
(12VC1).
10. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO:1 comprises a sequence where at least the following underlined amino acid residues of SEQ ID NO:1 are not replaced with a different amino acid residue:
(SEQ ID NO: 1)
VSSVPTKLE V VAATPTSLL I S W DAPAVTVF F Y V ITY G ET G HG VG A F Q AF
K VP G SKST A T I S GL K P GVD Y TIT VYARG YSK Q GPY KP S P ISINYRT
(12VC1).
11. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO: 1 conserves at least the following sequence from SEQ ID NO:1: VYARG.
12. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO: 1 has 91% homology to SEQ ID NO:1.
13. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO: 1 has 93% homology to SEQ ID NO:1.
14. The protein or peptide of claim 1 , wherein the variant of SEQ ID NO:1 has 95% homology to SEQ ID NO:1.
15. A composition comprising a protein or peptide according to claim 1 and a pharmaceutically acceptable carrier.
16. A fusion protein or proteolysis targeting chimera (PROTAC) comprising the protein or peptide according to claim 1 .
17. The fusion protein or PROTAC according to claim 16 , further comprising an E3 ligase subunit or fragment of an E3 subunit.
18. The fusion protein or PROTAC according to claim 17 , wherein the E3 ligase is Von Hippel-Lindau tumor suppressor (VHL), cereblon (CRBN), mouse double minute 2 (MDM2), cellular inhibitor of apoptosis (cIAP), and speckle-type POZ protein (SPOP).
19. A composition comprising a fusion protein or PROTAC according to claim 16 and a pharmaceutically acceptable carrier.
20. A protein or peptide comprising the following sequence or a truncated variant thereof, or having the following sequence or truncated variant thereof:
(SEQ ID NO: 26)
XXXVPTXLEVVAATXXSLLISWDAPAVTVXFYVIXYGETGHGVGAFXAF
XVXXXXSTATISGLXPGVDYTITVYARXXSKQGXYXPSPISINYRT,
wherein each X is a canonical or non-canonical amino acid and the truncated variant of SEQ ID NO:26 has up to the first four residues at the N-terminus removed.
21. The protein or peptide according to claim 20 , wherein the sequence is:
(SEQ ID NO: 27)
VSSVPTKLEVVAATPTSLLISWDAPAVTVXFYVIXYGETGHGVGAFXAFX
VXXSKSTATISGLKPGVDYTITVYARXXSKQGXYXPSPISINYRT
or a truncated variant thereof, or
(SEQ ID NO: 28)
XXXVPTXLEVVAATXXSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFK
VPGXXSTATISGLXPGVDYTITVYARGYSKQGPYKPSPISINYRT
or a truncated variant thereof,
wherein the truncated variant of SEQ ID NO:27 or the truncated variant of SEQ ID NO:28 has up to the first four residues at the N-terminus removed.
22. The protein or peptide according to claim 20 , wherein each X is individually chosen from alanine, serine, arginine, glutamine, asparagine, threonine, and tyrosine.
23. A protein or peptide comprising the following sequence:
VSSVPTKLEVVAATPTSLLISWDAPAVTVFFYVITYGETGHGVGAFQAFKVPGSKSTATIS GLKPGVDYTITVYARGYSKQGPYKPSPISINYRT (12VC1) (SEQ ID NO:1) or a truncated variant thereof, wherein the truncated variant has up to the first four residues at the N-terminus removed.Join the waitlist — get patent alerts
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